ABSTRACT ? OVERALL Sanford Burnham Prebys Medical Discovery Institute (SBP) is an independent nonprofit research and graduate degree-granting institution located in La Jolla, CA, that conducts laboratory-based biomedical research funded primarily through NIH grants. The mission of the SBP NCI-designated Cancer Center is to be a national leader in the effort to overcome cancer as a cause of human suffering and death. Our vision is to make paradigm- shifting discoveries that will underlie novel therapeutic modalities by creating, translating, and disseminating exceptional basic cancer science. We will attain this by: (1) conducting state-of-the-art, multidisciplinary basic research into the causes, prevention, and treatment of cancer; (2) advancing our discoveries into early preclinical development for the benefit of cancer patients everywhere; and (3) educating and training the next generation of cancer scientists. The CCSG proposal details our plans for advancing our early translational cancer research capabilities, including basic cancer discovery (novel gene targets and mechanisms), an area of long-standing exceptional strength at the Center. We will advance our scientific discoveries through several platforms, including small molecule-based drug discovery, an area in which we have significant technical capabilities and experience; and early preclinical therapeutic development, a growing strength. The Cancer Center is organized around three programs that encompass the cancer continuum: Tumor Initiation and Maintenance, Cancer Metabolism and Signaling Networks, and Tumor Microenvironment and Cancer Immunology, each having three sub-themes based on the hallmarks of cancer. We describe 10 Shared Resources that are critical for achieving the scientific goals of the programs with which they are tightly interwoven. We describe the past use of CCSG developmental funds for supporting the recruitment of new faculty and collaborative translational pilot projects. The San Diego NCI Cancer Center Council (C3) is a collaborative initiative between the three local NCI-designated Cancer Centers: SBP, UCSD, and the Salk Institute. The C3 initiative leverages the unique skills and resources of each cancer center for the treatment and ultimate cure of cancer by providing access to select shared resources at each institution at internal member rates, and outside philanthropic support for collaborative translational grants between investigators at the three cancer centers. The proposal highlights the progress made towards achieving our vision through multilevel strategic planning and evaluation, investments, recruitments, collaborations, organizational changes, and research accomplishments. Situated in San Diego, the fifth most populous county and the largest biotech and second largest life sciences cluster in the US, the Cancer Center is poised to achieve its vision by leveraging its scientific strengths through collaborations with academic and private sector investigators locally, nationally, and internationally.